Signs Point to Relationship Between Clopidogrel Efficacy, Cigarette Smoking

Evidence is mounting that clopidogrel therapy is less beneficial to nonsmoking patients, as outlined by a viewpoint published in the June 20, 2012, issue of the Journal of the American Medical Association. The authors express concern that the antiplatelet drug may not be the best choice in this patient group.

Paul A. Gurbel, MD, of Sinai Hospital of Baltimore (Baltimore, MD), and colleagues reviewed several studies published over the past few years that involved subsets of smoking and nonsmoking patients taking clopidogrel or placebo. Since cigarette smoking induces the activity of cytochrome P450 (CYP) 1A2, an isoenzyme involved in the metabolic activation of clopidogrel, nonsmokers have greater platelet reactivity than smokers during treatment, they assert.

In the CAPRIE (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events) trial, for example, a subanalysis found that patients in the clopidogrel group who did not smoke had no reduction in ischemic stroke, MI, or vascular death compared with nonsmokers who received aspirin. Yet among smokers, clopidogrel patients had a much lower risk of the composite outcome than did aspirin patients (8.3% vs. 10.8%; HR 0.76; 95% CI 0.64-0.90).

Other data suggesting clopidogrel’s protective effect in smokers come from the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events), CREDO (Clopidogrel for the Reduction of Events During Observation), CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy—Thrombolysis in Myocardial Infarction 28), CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance), and CURRENT-OASIS 7 (Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Symptoms) trials.

The adverse event risk was as much as 56% lower in smokers taking clopidogrel vs. placebo.

A Reason for Concern

“These large-scale clinical trials have led to the dominant use of clopidogrel in the treatment of high-risk patients with cardiovascular disease,” Dr. Gurbel and colleagues write. “However, evidence from these same studies consistently supports less or no clinical efficacy from clopidogrel therapy among patients who do not smoke. These observations raise concerns about the costs and potential risks incurred by treating nonsmokers with clopidogrel.”

In a telephone interview with TCTMD, Dr. Gurbel termed the data “sobering” and called for further research into the relationship between smoking and cytochrome interaction. He and his team plan to present findings from a recently completed pharmacodynamic study evaluating the influence of smoking on the antiplatelet effect of clopidogrel compared with prasugrel at the annual Transcatheter Cardiovascular Therapeutics scientific symposium this October in Miami, FL.

In addition, a forthcoming substudy of 3,000 patients from the TRILOGY trial who underwent serial platelet function testing will provide a “very robust assessment of smoking status, much better than what has been accomplished in all of the other trials that preceded it,” he reported.

Not a Pressing Issue?

But Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), told TCTMD in a telephone interview that for now the findings, while interesting, should not prompt a change in clinical practice.

“It’s always tempting to break down studies according to subgroups, but that’s a great way to generated false hypotheses,” he said. “Clopidogrel has been tested in large populations of patients with acute coronary syndromes, and it works.”

While it makes sense biologically that smoking would affect clopidogrel efficacy, Dr. Kleiman said, it would not make sense to eliminate P2Y12 antagonists from the treatment of nonsmokers. Rather, this information could be used as a “bargaining chip” for a smoker who does not want to take clopidogrel.

“I think we’re a long way from not treating patients who are nonsmokers based on these data or based on anything short of a real randomized trial in nonsmokers, which I don’t think anyone is eager to do,” he said. “It teaches us a lot about how the drugs work, . . . but is this going to have a direct impact? No.”

Dr. Kleiman advised that future research should focus on more pressing concerns like how long to continue antiplatelet therapy. “Learning more about how long to treat patients, learning which patients are at highest risk of long-term bleeding, and learning what to do with patients who need an oral anticoagulant are higher priority issues than whether to treat nonsmokers,” he concluded.

 

---

Source:
Gurbel PA, Nolin TD, Tantry US. Clopidogrel efficacy and cigarette smoking status. JAMA. 2012;307:2495-2496.

 

 

Related Stories:

• Better Clopidogrel Response Seen with Increased Smoking Levels
• Clopidogrel Response Affected by Smoking, Gender, and PPI Use
• Enhanced Benefit of Clopidogrel Seen in Moderate Smokers

Click here for a listing of companies that provide support to the Cardiovascular Research Foundation, owner and operator of TCTMD.